Geoff Kerchner, MD, PhD

“Crenezumab is actually the leading investigational therapy that directly targets that toxic form of Aβ."

Geoff Kerchner, MD, PhD, Senior Medical Director of Neuroscience at Genentech, sat down with 

at the 2018 Alzheimer Association International Conference in Chicago, Illinois, to discuss the characteristics from CREAD 1 and CREAD 2, 2 global, randomized, double-blind, placebo-controlled, parallel-group phase III studies testing the safety and efficacy of crenezumab 60 mg/kg in subjects with prodromal to mild Alzheimer disease.

Crenezumab, a humanized Aβ monoclonal IgG4 antibody, binds to multiple forms of Aβ with a high affinity for oligomers, blocking oligomer-induced neurotoxicity and with low risk of amyloid-related imaging abnormalities. Despite the co-primary endpoints of the phase II trial not being met, exploratory analyses suggest that crenezumab should be tested at a higher dose and earlier disease stage for clinically meaningful efficacy. Data from the phase Ib study which investigated the safety and tolerability of higher doses of crenezumab back a 4-fold higher phase III dose than previously used in phase II.

CREAD 1 and CREAD 2 will test whether clinically meaningful efficacy can be achieved without the associated safety findings that are reported with other passive anti-amyloid immunotherapies targeting fibrillar amyloid in Alzheimer disease.

Primary and secondary endpoints of CREAD 1 and CREAD 2 include change from baseline in CDR-SB, ADAS-cog-13 and ADCS-ADL scores over 105 weeks, and exploratory objectives include assessing treatment effects on CSF biomarkers and amyloid- and tau-Pet. The study has completed recruitment with 813 patients enrolled.

Kerchner also discussed the progress that has been made and his excitement for the future, emphasizing that previous trials have allowed researchers to learn that treating at a high dose and treating early are critical. He mentioned that there’s a wealth of knowledge that has helped to improve the design of clinical trials, maximizing the chances to show benefit for patients.

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Data back a 4-fold higher dose of crenezumab in the CREAD 1 and CREAD 2 trials than used in phase II.

Geoff Kerchner, MD, PhD: Phase III Trials of Crenezumab in Treatment of Prodromal to Mild Alzheimer

“We were able to show that gantenerumab is able to lower amyloid plaque levels in the brain, and as many as half of the people exposed to the drug for a couple of years actually showed complete clearing.”

At the 2018 Alzheimer’s Association International Conference in Chicago, Illinois, Geoff Kerchner, MD, PhD, senior medical director of neuroscience, Genentech, sat down with 

to discuss gantenerumab, an investigational, monoclonal antibody designed to bind to aggregated Aβ and remove beta plaques.

Based on previous studies, results show that gantenerumab was able to lower amyloid plaque levels in the brain and as many as half of study participants showed complete clearing of amyloid plaques.

The Marguerite RoAD and SCarlet RoAD studies, 2 prior phase III studies that were stopped prematurely due to evidence indicating the studies would not meet their primary endpoint, were turned into open-label extensions. The updated SCarlet RoAD open-label extension safety analysis reported no new or unexpected findings with a longer exposure to high-dose gantenerumab, however, the amyloid related imaging abnormalities-edema (ARIA-E) rate increased with the dose, but the titration appeared to reduce the risk with an overall incidence <30%. Kerchner emphasizes that the data from the Marguerite RoAD and SCarlet RoAD studies supports the use of titration to a higher dose of gantenerumab in the phase III GRADUATE program.

Gantenerumab is currently being investigated in 2 phase III studies, GRADUATE 1 and 2. The studies, currently enrolling participants with early Alzheimer disease with confirmed Alzheimer disease pathology, will include higher doses of gantenerumab, about 5 times the dose that was given in the Marguerite RoAD and SCarlet RoAD studies. Subjects will be on double-blind treatment for 2 years. Target dose is achieved through a titration regimen in order to best optimize safety.

Higher doses of gantenerumab, a monoclonal antibody designed to bind to aggregated Aβ and remove beta plaques, will be investigated in phase III trials.

Geoff Kerchner, MD, PhD

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Geoff Kerchner, MD, PhD: Phase III Trials of Crenezumab in Treatment of Prodromal to Mild Alzheimer

Geoff Kerchner, MD, PhD: Gantenerumab as Disease-Modifying Treatment in Early Alzheimer Disease